Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis

Valerian E. Kagan, Gaowei Mao, Feng Qu, Jose Pedro Friedmann Angeli, Sebastian Doll, Claudette St Croix, Haider Hussain Dar, Bing Liu, Vladimir A. Tyurin, Vladimir B. Ritov, Alexandr A. Kapralov, Andrew A. Amoscato, Jianfei Jiang, Tamil Anthonymuthu, Dariush Mohammadyani, Qin Yang, Bettina Proneth, Judith Klein-Seetharaman, Simon Watkins, Ivet BaharJoel Greenberger, Rama K. Mallampalli, Brent R. Stockwell, Yulia Y. Tyurina, Marcus Conrad, Hülya Baylr

Research output: Contribution to journalArticlepeer-review

587 Scopus citations

Abstract

Enigmatic lipid peroxidation products have been claimed as the proximate executioners of ferroptosis-a specialized death program triggered by insufficiency of glutathione peroxidase 4 (GPX4). Using quantitative redox lipidomics, reverse genetics, bioinformatics and systems biology, we discovered that ferroptosis involves a highly organized oxygenation center, wherein oxidation in endoplasmic-reticulum-associated compartments occurs on only one class of phospholipids (phosphatidylethanolamines (PEs)) and is specific toward two fatty acyls-arachidonoyl (AA) and adrenoyl (AdA). Suppression of AA or AdA esterification into PE by genetic or pharmacological inhibition of acyl-CoA synthase 4 (ACSL4) acts as a specific antiferroptotic rescue pathway. Lipoxygenase (LOX) generates doubly and triply-oxygenated (15-hydroperoxy)-diacylated PE species, which act as death signals, and tocopherols and tocotrienols (vitamin E) suppress LOX and protect against ferroptosis, suggesting a homeostatic physiological role for vitamin E. This oxidative PE death pathway may also represent a target for drug discovery.

Original languageEnglish (US)
Pages (from-to)81-90
Number of pages10
JournalNature Chemical Biology
Volume13
Issue number1
DOIs
StatePublished - Jan 1 2017
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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